Compound consisting of proton pump inhibitor and gastric mucosa protective agent and application thereof
Technical Field
The invention belongs to the field of medicines for treating digestive system diseases, and particularly relates to a compound consisting of a proton pump inhibitor and a gastric mucosa protective agent and application thereof.
Background
Digestive system diseases are common diseases, the course of diseases is chronic and has the characteristic of repeated attack, the total incidence rate accounts for 10-20% of the total population, and the main diseases comprise acute gastritis, chronic gastritis, peptic ulcer, functional dyspepsia and the like. Functional dyspepsia and peptic ulcer are the most common of them.
Peptic ulcer refers to mainly chronic ulcer occurring in stomach and duodenum, i.e. gastric ulcer and duodenal ulcer, and is named because the occurrence and formation of ulcer are related to the digestive action of gastric acid-pepsin. The symptoms at the initial stage of the disease are similar to the symptoms of functional dyspepsia, such as chronic or periodic pain, gastrectasia, warm air, acid regurgitation and the like in the stomach area, and abdominal pain, black stool, hematemesis and the like in severe cases. The specific pathogenesis of the medical community is now under study discussion and is currently believed to be related to the imbalance between the offending factors responsible for ulceration and the defense factors of the mucosa. Attacking factors include gastric acid, pepsin, regurgitated bile, etc.; defensive factors include mucus barrier, mucosal repair function, and the like. The factors causing the digestive tract ulcer mainly include working tension, fatigue, irregular diet, excessive medicine for stimulating the gastrointestinal tract, life habits, psychological states and the like.
At present, the medicines for treating the peptic ulcer mainly comprise two types, namely gastric acid reducing medicines (weakening attack factors) and mucosa protecting medicines (strengthening defense factors). Among them, gastric acid-lowering drugs are mainly based on proton pump inhibitors in clinical practice. The action mechanisms of the medicaments for protecting the mucous membrane are different, but the medicaments have the function of protecting gastric mucous membrane cells.
Proton Pump Inhibitors (PPIs) are drugs for inhibiting gastric acid secretion, also called H + -K + ATPase inhibitors, and can specifically and non-competitively act on the end link of gastric acid secretion, namely H + -K + ATPase on gastric parietal cells. Currently, the related diseases clinically treated by the proton pump inhibitor are mainly as follows: peptic ulcer, helicobacter pylori infection, gastroesophageal reflux disease, upper gastrointestinal hemorrhage, Zollinger-Ellison syndrome, non-steroidal anti-inflammatory drug (NSAIDS) -related ulcer, dyspepsia, stress ulcer, Barrett esophagus, etc. The domestic approved products on the market of proton pump inhibitors include: omeprazole, pantoprazole, lansoprazole, rabeprazole, esomeprazole, and the like.
The proton pump inhibitor has the following defects:
the effect is slow. The maximum acid inhibition effect can be achieved after the medicine is taken for 3-5 days.
② the acid suppression is unstable. Long-term treatment with PPIs still does not achieve a balanced gastric acid suppression at 24h throughout the day and can therefore cause a range of symptoms.
③ the PPIs have larger individual difference in treatment. PPIs are mainly metabolized by enzymes of hepatocyte cytochrome P450(CYP)2C19, and for slow metabolizers with CYP2C19 gene mutation, the clearance rate of PPIs is reduced, and the medicine effect is unstable.
Safety has attracted attention. In recent years, the drug supervision and management departments in the United states and European Union successively release safety information about proton pump inhibitor drugs, warn the risks of fracture, hypomagnesemia and the like of the drugs and the drug interaction with clopidogrel, and revise the drug specifications.
Fifthly, the acid inhibition is not thorough, which shows the phenomenon of acid breakthrough at night; in addition, long-term inhibition of gastric acid secretion by PPIs may cause hypergastrinemia, which further leads to gastric mucosa or precancerous lesion of gastric cancer.
In recent years, the importance of enhancing the defense function of the gastric mucosa has been recognized, and it is considered that enhancing the gastric mucosa protection plays a positive role in the healing of ulcers. The action mechanisms of the drugs are different. The main representatives of this class of drugs are: prostaglandins, teprenone, sucralfate, bismuth potassium citrate, etc.
1) Prostaglandins
The stomach mucosa epithelial cells continuously synthesize and release endogenous Prostaglandin (PG), and have strong protection effect on the stomach mucosa epithelial cells. In recent years, PG medicines are found to be capable of binding with specific receptors on cell membranes to block gastric acid secretion. Representative drugs include roxaprost, misoprostol, enprost, onoprost, and the like. The PG type preparations are particularly suitable for ulcers or stress ulcers caused by non-steroidal anti-inflammatory drugs.
2) Teprenone
The product is a novel gastric mucosa protective agent for directly increasing mucus secretion and promoting cell regeneration, promoting gastric mucus secretion, maintaining normal structure and function of mucus and running water layer, and promoting replication of mucosal epithelial cell, thereby relieving gastric mucosa injury, and recovering injured gastric mucosa even ulcer. Has direct protection effect on gastric mucosa. Can be used for treating peptic ulcer, chronic gastritis, and stomach mucosa injury induced by NSAID in clinic.
3) Sucralfate
Sucralfate can decompose sucrose octasulfate anion complex in acidic gastric juice, and can combine with protein with positive charge on ulcer surface to form protective barrier, adsorb bile salt and bile acid, and prevent erosion of gastric acid and pepsin. Meanwhile, sucralfate can increase secretion of gastrointestinal mucus and bicarbonate, inhibit acid diffusion, reduce pepsin concentration in gastric juice and inhibit activity of pepsin. In addition, when the helicobacter pylori is eradicated, sucralfate can delay the elimination of antibiotics in the gastrointestinal tract and inhibit the absorption and degradation of the antibiotics, so that the concentration of the antibiotics is increased, and a complex formed by the sucralfate and the antibiotics is directly accumulated on the surface of the helicobacter pylori, thereby increasing the eradication rate of the helicobacter pylori.
4) Bismuth agent
The bismuth agent is a gastric mucosa protective agent which is paid much attention in recent years, and the main action mechanism comprises (1) under the environment of gastric acid pH, colloidal bismuth forms a firm bismuth oxide colloidal precipitate on the ulcer surface or ulcer substrate granulation tissue to form a protective film to isolate the invasion of irritative substances such as gastric acid, pepsin, bile salt, food and the like on gastric mucosa; (2) can promote the synthesis of PGE2 of gastric mucosa and the secretion of bicarbonate, improve the blood circulation of gastric mucosa and enhance the defense function of gastric mucosa; (3) delay the degradation of epidermal growth factor and promote the surface epithelial proliferation. Accelerate the repair and healing of ulcer tissues; (4) the bismuth preparation has strong inhibiting effect on helicobacter pylori, and is beneficial to improving the healing rate of peptic ulcer and reducing the recurrence rate. The commonly used medicines comprise bismuth potassium citrate, colloidal bismuth pectin, bismuth citrate ranitidine and the like. The bismuth preparation has low toxic and side effects, and does not affect liver, kidney and nervous system, but the stool may appear dark brown during administration.
In order to improve the therapeutic effect on diseases of the digestive system, CN104225596 discloses a pharmaceutical composition for the treatment of gastritis and gastric ulcer, which comprises a proton pump inhibitor and a gastric mucosa protective agent, wherein the gastric mucosa protective agent is preferably allantoin. The composition has not ideal curative effect on peptic ulcer and gastrointestinal hemorrhage, and has slow effect and serious peak-valley phenomenon.
Disclosure of Invention
In order to solve the technical problems, the invention provides a compound consisting of a proton pump inhibitor and a gastric mucosa protective agent, which has good treatment effect on peptic ulcer and digestive tract bleeding, low administration frequency, short administration time and long onset time.
The invention provides a compound consisting of a proton pump inhibitor and a gastric mucosa protective agent, which comprises the proton pump inhibitor and the gastric mucosa protective agent, wherein the molar ratio of the proton pump inhibitor to the gastric mucosa protective agent is 1-2:1-2, and the proton pump inhibitor is selected from omeprazole, pantoprazole, lansoprazole, rabeprazole, ilaprazole, esomeprazole, levo-pantoprazole, dextro-lansoprazole or dextro-rabeprazole; the gastric mucosa protective agent is selected from prostanoid, teprenone, sucralfate or bismuth potassium citrate.
In a further improvement, the gastric mucosa protective agent is prostaglandin or teprenone.
In a further improvement, the proton pump inhibitor is levo-pantoprazole, dextro-lansoprazole or dextro-rabeprazole.
In a further improvement, the gastric mucosa protective agent is teprenone, and the proton pump inhibitor is dextro-rabeprazole.
In a further improvement, the proton pump inhibitor and gastric mucosa protectant are linked by hydrogen bonding.
In a further improvement, the compound is a co-crystallized sodium salt hydrate, and the general formula of the co-crystallized sodium salt hydrate is (dextro-rabeprazole-hydrogen bond-teprenone) ∙ 2Na ∙ 1H2O, the co-crystallized sodium salt hydrate has characteristic peaks at 7.5 °, 12.4 °, 18.4 °, 22.3 °, 25.8 ° and 33.7 ° in X-ray diffraction expressed in 2 θ.
In another aspect, the present invention provides a method for preparing a co-crystalline sodium salt hydrate, comprising the steps of:
s1: dissolving 1mol of dextro-rabeprazole and 1mol of teprenone in 50mL of mixed solution of water and ethanol with the volume ratio of 1:2.5, wherein the concentration of sodium ethoxide in the mixed solution is 0.15 mol/mL;
s2: standing at-10 deg.C, crystallizing, and naturally drying.
The invention also provides a microsphere tablet, which comprises the compound and an auxiliary material, wherein the weight part ratio of the compound to the auxiliary material is 1: 1-2.5; the auxiliary materials comprise the following components in parts by weight:
5-10 of polylactic glycolic acid
1-2.5 of pregelatinized starch particles.
According to the invention, polylactic glycolic acid and pregelatinized starch particles are added into the microsphere tablet to form microspheres with the compound, so that the stability of the microsphere tablet can be obviously improved, and the prepared microsphere tablet can be slowly released within 24h to play a long-acting role.
In a further improvement, the auxiliary materials also comprise the following components in parts by weight:
polypropylene dextran 3-8
0.5-1 part of sodium alginate.
The invention further adds the mixture of the polypropylene glucan and the sodium alginate into the auxiliary material, and the mixture can be further included on the surface of the microsphere, thereby improving the drug loading rate and the encapsulation rate of the microsphere tablet.
In a further improvement, the pregelatinized starch particles are prepared from the following components in parts by weight:
pregelatinized starch 7-8
Polyethylene glycol 6000.5-1.
In another aspect, the present invention provides a method for preparing pregelatinized starch particles, the method comprising the steps of:
s11: dissolving 7-8g of pregelatinized starch in 50mL of mixed solution of water and ethanol with the volume ratio of 1:1 to prepare mixed solution;
s12: putting the mixed solution prepared in the step S11 at 5000 r.min-1Stirring to form emulsion;
s13: adding 3.7% formaldehyde solution into the emulsion obtained in step S12, solidifying, centrifuging, washing with distilled water until no formaldehyde smell is produced, filtering, and drying to obtain pregelatinized starch particles with particle size of 5-10 μm.
In another aspect, the present invention provides a method for preparing a microsphere tablet, the method comprising the steps of:
1) dissolving polylactic glycolic acid and 3/4 parts by weight of pregelatinized starch particles in water to prepare an aqueous solution;
2) dissolving the compound and the rest of pregelatinized starch particles in the ethanol to prepare ethanol solution;
3) adding the ethanol solution obtained in the step S2 into the aqueous solution obtained in the step S1, and stirring for 1600r min-1Stirring to form emulsion;
4) controlling the temperature of the emulsion to be lower than 20 ℃, continuously stirring, and volatilizing ethanol until the microspheres are solidified to prepare microspheres;
5) dissolving polypropylene dextran and sodium alginate in water to obtain water solution;
6) dissolving the microspheres prepared in the step 4) in the aqueous solution prepared in the step 5), stirring for 30min at 20 ℃ and at the rotating speed of 50 r/min, centrifuging for 2min at 500 r/min, and curing to prepare double-layer microspheres;
7) tabletting the double-layer microspheres to obtain the tablet.
The invention also provides the application of the compound in preparing medicines for treating peptic ulcer and gastrointestinal hemorrhage.
The invention has the beneficial effects that the invention provides a compound consisting of a proton pump inhibitor and a gastric mucosa protective agent and application thereof, the proton pump inhibitor and the gastric mucosa protective agent are combined together in a mode of direct mixing or indirect connection through hydrogen bonds, and the sodium cocrystallite hydrate formed by the hydrogen bond connection has more stable property and obviously provides pharmacokinetic property; although the action mechanisms of the two are different, the complex formed by the two has unexpected synergistic effect, and has positive application prospect in the treatment field of peptic ulcer and gastrointestinal hemorrhage.
The compound indirectly connected through hydrogen bonds also overcomes various defects of the existing proton pump inhibitor in pharmacodynamics and pharmacokinetics, and has good clinical prospect.
Drawings
FIG. 1 is an X-ray diffraction pattern of a co-crystalline sodium salt hydrate;
FIG. 2 shows the results of in vitro release test of microsphere tablets.
Detailed description of the preferred embodiments
EXAMPLE 1A Complex of a proton Pump inhibitor and a gastric mucosal protective agent
The compound comprises 1mol of dextro-rabeprazole and 1mol of teprenone.
EXAMPLE 2A Complex of a proton Pump inhibitor and a gastric mucosal protective agent
The compound comprises 1mol of dexlansoprazole and 1mol of teprenone.
EXAMPLE 3A Complex of a proton Pump inhibitor and a gastric mucosal protective agent
The compound comprises 1mol of levo-pantoprazole and 1mol of teprenone.
EXAMPLE 4A Complex of a proton Pump inhibitor and a gastric mucosal protective agent
The compound comprises 1mol of dextro-rabeprazole and 1mol of prostaglandin.
EXAMPLE 5A Complex of a proton Pump inhibitor and a gastric mucosal protective agent
The compound comprises 1mol of dexlansoprazole and 2mol of sucralfate.
EXAMPLE 6A Complex of a proton Pump inhibitor and a gastric mucosal protective agent
The compound comprises 1mol of dexlansoprazole and 1mol of bismuth potassium citrate.
EXAMPLE 7A Complex of a proton Pump inhibitor and a gastric mucosal protective agent
The compound comprises 1mol of dextro-rabeprazole and 1mol of misoprostol.
EXAMPLE 8A Complex of a proton Pump inhibitor and a gastric mucosal protective agent
The compound comprises 1mol of dextro-rabeprazole and 1mol of enprostil.
EXAMPLE 9A Complex of a proton Pump inhibitor and a gastric mucosal protective agent
The compound comprises 1mol of esomeprazole and 1mol of teprenone.
EXAMPLE 10A Complex of a proton Pump inhibitor and a gastric mucosal protective agent
The compound comprises 1mol of levo-pantoprazole and 1mol of prostaglandin.
EXAMPLE 11A Complex of a proton Pump inhibitor and a gastric mucosal protective agent
The compound comprises 1mol of ilaprazole and 2mol of teprenone.
EXAMPLE 12A Complex of a proton Pump inhibitor and a gastric mucosal protective agent
The compound comprises 1mol of esomeprazole and 1mol of teprenone.
EXAMPLE 13A Complex of a proton Pump inhibitor and a gastric mucosal protective agent
The compound comprises 1mol of ilaprazole and 1mol of teprenone.
EXAMPLE 14A Complex of a proton Pump inhibitor and a gastric mucosal protective agent
The compound is a co-crystallized sodium salt hydrate, and the general formula of the co-crystallized sodium salt hydrate is (dextro-rabeprazole-hydrogen bond-teprenone) ∙ 2Na ∙ 1H2O, the co-crystalline sodium salt hydrate has characteristic peaks at 7.5 °, 12.4 °, 18.4 °, 22.3 °, 25.8 ° and 33.7 ° in X-ray diffraction expressed in 2 θ, as shown in fig. 1, and the relative intensities of the above characteristic peaks are as follows:
2θ
|
relative Strength (%)
|
7.5°
|
42
|
12.4°
|
25
|
18.4°
|
100
|
22.3°
|
68
|
25.8°
|
34
|
33.7°
|
82 |
EXAMPLE 15 microsphere tablets
The dosage of each component of the microsphere tablet is as follows:
example 1 Complex 10g
Polylactic glycolic acid 7.5g
Pregelatinized starch particles 2.5 g.
EXAMPLE 16 microsphere tablet
The dosage of each component of the microsphere tablet is as follows:
example 2 Complex 10g
11.25g of polylactic glycolic acid
Pregelatinized starch microparticles
Pregelatinized starch 3.5g
6000.25 g of polyethylene glycol.
EXAMPLE 17 microsphere tablet
The dosage of each component of the microsphere tablet is as follows:
example 14 Complex 10g
Polylactic glycolic acid 16.5g
Pregelatinized starch microparticles
Pregelatinized starch 3.2g
6000.4 g of polyethylene glycol.
EXAMPLE 18 microsphere tablets
The dosage of each component of the microsphere tablet is as follows:
EXAMPLE 19 microsphere tablet
The dosage of each component of the microsphere tablet is as follows:
EXAMPLE 20 microsphere tablets
The dosage of each component of the microsphere tablet is as follows:
example 14 Complex 10g
11.2g of polylactic glycolic acid
Pregelatinized starch microparticles
Comparative example 1A Complex of a proton Pump inhibitor and a gastric mucosal protective agent
The compound comprises 1mol of dextro-rabeprazole and 1mol of allantoin.
Comparative example 2 microsphere tablet
The dosage of each component of the microsphere tablet is as follows:
example 1 Complex 10g
Polyvinyl alcohol 7.5g
Pregelatinized starch particles 2.5 g.
Comparative example 3 microsphere tablet
The dosage of each component of the microsphere tablet is as follows:
example 1 Complex 10g
Polylactic glycolic acid 7.5g
Pregelatinized starch 2.5 g.
Comparative example 4 microsphere tablet
The dosage of each component of the microsphere tablet is as follows:
example 14 Complex 10g
11.2g of polylactic glycolic acid
Pregelatinized starch microparticles
Test example 1 stability test
1.1 accelerated test
The microsphere tablets of example 16, example 20 and comparative examples 2 to 4 of the present invention were all placed at 40 ℃ ± 2 ℃ under a relative humidity of 75% ± 5% for 6 months, and were sampled once at the end of 1 month, 2 months, 3 months and 6 months during the test period, and the properties of the microsphere tablets, the content of dextro-rabeprazole (labeled amount%), and the encapsulation rate (%) were measured according to the specifications in the chinese pharmacopoeia, and the results are shown in table 1.
TABLE 1 accelerated test results for microsphere tablets
As can be seen from the table, the microsphere tablets provided in examples 16 and 20 of the present invention have no significant change in properties, amount of dextro-rabeprazole and encapsulation efficiency after being placed for 6 months, as can be seen from the results of accelerated tests; after the microsphere tablets in the comparative examples 2-4 are placed for 6 months, the microsphere tablets are yellowed, the content of the dextro-rabeprazole is obviously reduced, and the encapsulation efficiency is obviously reduced; the microsphere tablets of the invention are shown to have significantly improved stability compared to control examples 2-4; and it can be seen from the above table that the encapsulation efficiency of example 20 is significantly higher than that of example 16 and comparative example 4, while the encapsulation efficiency of example 16 is significantly higher than that of comparative examples 2 and 3, so that it is concluded that the addition of polypropylene dextran and sodium alginate in the adjuvant can significantly improve the encapsulation efficiency of the microspheres, and the addition of other mixtures has no significant effect on the improvement of the encapsulation efficiency.
1.2 Long term test
The microsphere tablets of example 16, example 20 and comparative examples 2 to 4 were all placed at 25 ℃ ± 2 ℃ and a relative humidity of 60% ± 10% for 12 months, and sampled every 3 months, and sampled at 0 month, 3 months, 6 months, 9 months, 12 months and 24 months, respectively, to test the properties of the microsphere tablets, the content (labeled amount%) of dextrorabeprazole and the encapsulation efficiency (%), and the results are shown in table 2.
TABLE 2 Long-term test results for microsphere tablets
It can be seen from the table that, according to the microsphere tablets provided in examples 16 and 20 of the present invention, long-term test results show that, after being placed for 24 months, the properties, the amount of the dextro-rabeprazole and the encapsulation efficiency of the microsphere tablets do not change significantly; after the microsphere tablets in the comparative examples 2-4 are placed for 24 months, the microsphere tablets are yellowed, the content of the dextro-rabeprazole is obviously reduced, and the encapsulation efficiency is reduced; the microsphere tablets of the invention are shown to have significantly improved stability compared to the microsphere tablets of comparative examples 2-4; and it can be seen from the above table that the encapsulation efficiency of example 20 is significantly higher than that of example 16 and comparative example 4, while the encapsulation efficiency of example 16 is significantly higher than that of comparative examples 2 and 3, so that it is concluded that the addition of polypropylene dextran and sodium alginate in the adjuvant can significantly improve the encapsulation efficiency of the microspheres, and the addition of other mixtures has no significant effect on the improvement of the encapsulation efficiency.
Test example 2 in vitro Release assay
And (3) detecting the drug release rate, namely referring to the examination of the in vitro drug release rate in appendix XIXD of Chinese pharmacopoeia of 2010 version.
The microsphere tablets of example 16 and comparative examples 2 to 3 were taken, respectively, and placed in a drug dissolution apparatus, and samples were taken for 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 16 hours, and 24 hours, respectively, and the dissolution percentage was measured by high performance liquid chromatography, and the cumulative release percentage of the drug was calculated, and the results are shown in fig. 2.
From the figure it can be seen that the microsphere tablet of example 16, released slowly over 24 h.
Test example 3 pharmacokinetic experiment
3.1 inhibitory Effect of Complex on mouse gastric ulcer caused by Anhydrous ethanol
1. Ulcer model building and grouping
Selecting 90 ICR mice, each half of the mice being female and male, randomly dividing the mice into 9 groups: a normal saline group (administration of an equal volume of normal saline), a model group (administration of an equal volume of normal saline), a group 1 (gavage administration of dextrorabeprazole at a dose of 10mg/kg), a group 2 (gavage administration of the compound of example 1 at a dose of 10mg/kg), a group 3 (gavage administration of the compound of example 2 at a dose of 10mg/kg), a group 4 (gavage administration of the compound of example 3 at a dose of 10mg/kg), a group 5 (gavage administration of the compound of example 4 at a dose of 10mg/kg), a group 6 (gavage administration of the compound of example 14 at a dose of 10mg/kg), and a group 7 (gavage administration of the compound of comparative example 1 at a dose of 10 mg/kg); continuously administering for 7 days, and 1ml/20g of absolute ethanol except physiological saline group after 1h of the last administration. Removing cervical vertebrae after 1h, killing, laparotomy, ligating cardia and pylorus respectively, taking out stomach, injecting 10% formaldehyde 6ml into stomach, placing whole stomach in formaldehyde solution, fixing for 30min, cutting along the greater curvature of stomach, washing with normal saline, and sucking water with filter paper. The maximum major axis and the maximum width of the gastric ulcer surface were measured by a vernier caliper, and the product of the two was used as an ulcer index to calculate the ulcer inhibition rate (%) (ulcer index of model group-ulcer index of administration group)/ulcer index of model group × 100%.
2. Data processing: data are averaged. + -. standard deviation
And (4) showing. The differences between groups were compared using the t-test.
3. Results
The results of the groups on the gastric ulcer of the mice caused by absolute ethyl alcohol are shown in table 3.
Table 3 results of groups on gastric ulcer in mice caused by absolute ethanol
P in comparison with group 1#<0.01,p%< 0.05, p compared to the group of 7 administered@< 0.01, p compared to group 2 administered*<0.05,p&<0.05。
Compared with the administration group 1 and the administration group 7, the compound provided by the invention can obviously reduce the ulcer index of mice, thereby obtaining that the treatment effect of the compound provided by the invention on the gastric ulcer of the mice is obviously improved compared with the administration of a proton pump inhibitor or a compound consisting of the proton pump inhibitor and allantoin, the inhibition rate of the compound consisting of the dextro-rabeprazole and the teprenone provided by the invention on the gastric ulcer is obviously higher than that of other compounds, and the treatment effect of the sodium co-crystal hydrate provided by the invention on the gastric ulcer is higher than that of other compounds.
3.2 inhibitory Effect of Complex on Experimental duodenal ulcer in rats
1. Ulcer model building and grouping
Selecting 90 SD rats with the weight of 160-200g, wherein the SD rats are half female and half male, and fasting is not forbidden for 24 hours before the experiment; after weighing the tags, they were randomly divided into 9 groups: a blank control group (to which an equal volume of carboxymethylcellulose is administered), a model control group (to which an equal volume of carboxymethylcellulose is administered), a group 1 (to which dextrorabeprazole is gavaged and at an administration dose of 10mg/kg), a group 2 (to which the compound of example 1 is gavaged and at an administration dose of 10mg/kg), a group 3 (to which the compound of example 2 is gavaged and at an administration dose of 10mg/kg), a group 4 (to which the compound of example 3 is gavaged and at an administration dose of 10mg/kg), a group 5 (to which the compound of example 4 is gavaged and at an administration dose of 10mg/kg), a group 6 (to which the compound of example 14 is gavaged and at an administration dose of 10mg/kg), and a group 7 (to which the compound of control 1 is gavaged and at an administration dose of 10 mg/kg); the administration is carried out for 1h or 10% cysteamine is subcutaneously injected respectively, and the dosage is 280 mg/kg. After 24h, one common carotid artery was isolated under ether anesthesia, and about 3ml of blood was taken for gastrin detection. Then, the rat is sacrificed by cervical dislocation, the abdomen is dissected, the cardia and the pyloric ring are ligated, the stomach and duodenum are removed, gastric juice is collected, the specimen is cut along the greater curvature of the stomach and the opposite side of the mesentery of the duodenum, the formation of duodenal ulcer is observed, and the ulcer area is measured.
2. Data processing: data are averaged. + -. standard deviation
And (4) showing. The differences between groups were compared using the t-test.
3. Results
The results for each group of experimental duodenal ulcers are shown in table 4.
Table 4 results of experimental duodenal ulcer in rats for each group
P in comparison with group 1%< 0.01, p compared to the group of 7 administered#<0.05,p*< 0.01, p compared to group 2 administered&<0.05,p#<0.05。
Compared with the administration group 1 and the administration group 7, the compound provided by the invention can obviously reduce the duodenal ulcer area of mice, and therefore, compared with the compound which is singly administered with a proton pump inhibitor or the compound which is composed of the proton pump inhibitor and allantoin, the compound provided by the invention has obviously improved treatment effect on the duodenal ulcer of the mice, the compound which is composed of the dextro-rabeprazole and the teprenone provided by the invention has obviously higher treatment effect on the duodenal ulcer than other compounds, and the sodium cocrystallate hydrate provided by the invention has higher treatment effect on the duodenal ulcer than other compounds.
3.3 Effect of the Complex on bleeding from the digestive tract in mice
1. The method comprises the following steps: 90 mice, each half of male and female, weighing 20g, were randomly divided into 9 groups of 90 mice each, blank control group, model control group and 1-7 groups administered. Before the experiment, mice are fasted for 24 hours, and are injected with indomethacin by an intraperitoneal injection way according to 0.1mL/10 g. After 0.5h, 1 group (dexrabeprazole administration by gavage, administration dose of 5mg/kg), 2 groups (compound of example 1 administration by gavage, administration dose of 5mg/kg), 3 groups (compound of example 2 administration by gavage, administration dose of 5mg/kg), 4 groups (compound of example 3 administration by gavage, administration dose of 5mg/kg), 5 groups (compound of example 4 administration by gavage, administration dose of 5mg/kg), 6 groups (compound of example 14 administration by gavage, administration dose of 5mg/kg) and 7 groups (compound of comparative example 1 administration by gavage, administration dose of 5mg/kg) were administered. Repeating the intragastric administration for 1 time after 3h, and after 2 nd intragastric administration for 2.5h, intragastric administration of 50% ethanol according to the ratio of 0.1mL/10kg for each group of mice, after 1h, removing cervical vertebrae to kill the mice, dissecting and taking out the stomach, cleaning the stomach contents with normal saline, fixing in 10% formalin solution, taking out gastrointestinal tissues after 1h, and calculating the bleeding area.
2. Data processing: data are averaged. + -. standard deviation
And (4) showing. The differences between groups were compared using the t-test.
3. Results
The results of the treatment of the gastrointestinal bleeding by each group are shown in table 5.
TABLE 5 results of treatment of gastrointestinal hemorrhage in mice
P in comparison with group 1%< 0.01, p compared to the group of 7 administered#<0.05,p*< 0.01, p compared to group 2 administered&<0.01,p#<0.01。
Compared with the administration group 1 and the administration group 7, the compound provided by the invention can obviously reduce the gastrointestinal bleeding area of mice, so that the treatment effect of the compound on the gastrointestinal bleeding of the mice is obviously improved compared with the compound consisting of a proton pump inhibitor or the proton pump inhibitor and allantoin, the treatment effect of the compound consisting of the dextro-rabeprazole and the teprenone on the gastrointestinal bleeding of the mice is obviously higher than that of other compounds, and the treatment effect of the sodium cocrystallate hydrate on the gastrointestinal bleeding is higher than that of other compounds.